QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia.
Charles Perkins Centre, School of Life and Environmental Science, The University of Sydney, Sydney 2006, NSW, Australia.
Cell. 2021 Apr 15;184(8):2167-2182.e22. doi: 10.1016/j.cell.2021.03.026. Epub 2021 Mar 16.
Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.
在 COVID-19 患者中会发生心脏损伤和功能障碍，并增加死亡率。其病因尚未明确，但可能是通过直接的心脏感染和/或炎症诱导的功能障碍所致。为了确定机制和心脏保护药物，我们使用了一种结合人类心脏类器官与磷酸蛋白质组学和单核 RNA 测序的最先进的方法。我们发现了一种炎症“细胞因子风暴”，即干扰素 γ、白细胞介素 1β 和聚（I:C）的混合物，可诱导舒张功能障碍。溴结构域蛋白 4 被激活，同时还存在一种病毒反应，这在人类心脏类器官（hCO）和 SARS-CoV-2 感染的 K18-hACE2 小鼠心脏中都是一致的。溴结构域和末端蛋白家族抑制剂（BETi）可恢复 hCO 的功能障碍，并可完全预防细胞因子风暴小鼠模型中的心脏功能障碍和死亡。此外，BETi 可降低病毒反应中基因的转录，降低 ACE2 的表达，并减少 SARS-CoV-2 对心肌细胞的感染。总之，BETi，包括美国食品和药物管理局（FDA）突破性指定药物阿帕他隆，是预防 COVID-19 介导的心脏损伤的有希望的候选药物。
